CN1216594C - 包含奥卡西平的混悬液 - Google Patents
包含奥卡西平的混悬液 Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
- A61P25/12—Antiepileptics; Anticonvulsants for grand-mal
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Abstract
本发明提供了包含奥卡西平的混悬液形式的药物组合物。
Description
本发明涉及奥卡西平(Trileptal)的口服混悬液制剂。
奥卡西平(10,11-二氢-10-氧代-5H-二苯并[b,f]氮杂-5-甲酰胺)是一种已知的抗惊厥药,用于治疗因例如癫痫发作造成的抽搐。在例如,德国专利2,011,087中描述了其制备方法。
奥卡西平的口服混悬液形式是本领域已知的。它们是为了获得例如用于儿科使用和用于吞咽片剂困难的患者的其它剂型而被开发的。
我们发现,长期存储后市售混悬液中出现未预料到的高粘度/揺溶的,例如高粘度和不易流动现象,并变为褐色。这种不易流动现象在“成块”时愈发明显,只有通过极为剧烈的振摇才能够被困难地重新分散。变为褐色的原因是作为抗氧化剂加入的抗坏血酸形成了降解产物。
在深入试验后,我们惊奇地发现,可以制备具有改良物化性质的奥卡西平口服混悬液形式,以致极大地方便患者,如癫痫儿童或吞咽片剂困难的成人的使用。
第一方面,本发明涉及混悬液形式的、稳定而易于倾倒的药物组合物,该组合物包含奥卡西平并且振摇后具有5-52mPa.s.、如10-40mPa.s或10-30mPa.s、如10-25mPa.s的粘度。
“振摇”应理解为在使用前振摇,例如由患者用手剧烈振荡5-30秒。
粘度可以通过例如使用Haake VT 550粘度计(西尔操作原则)测量。例如,使用梭型NV并将剪切速度设定为1000s-1。测量温度为20℃。样品在装入量杯前例如用手作剧烈振摇。然后在装入后直接进行测量。读取数据前可以以1000s-1搅拌混悬液5分钟。
再一方面,本发明涉及混悬液形式的药物组合物,其包含奥卡西平和一或多种纤维素聚合物或它们的混合物,例如包含羧甲基纤维素(如其钠盐)和微晶纤维素的混合物,所述混合物占总组合物的1.25-1.95%(g/ml)、例如1.35-1.65%、如1.5%。优选地,混合物中羧甲基纤维素与微晶纤维素的比为1∶5至1∶12,如1∶8至1∶10。可以使用分散性纤维素,例如已知的商品名是AvicelRC,如AvicelRC 591(可以从如美国FMC公司购得)的分散性纤维素,作为一种优选的混合物。AvicelRC 591表现出以下特征:羧甲基纤维素钠含量在约8.3至约13.8%、粘度在约39至91cps、干燥后损失不超过6%、重金属不超过0.001%、pH在约6到约8、燃烧后残渣不超过5%(厂家信息)。
本发明混悬液提供了多种优点,包括甚至在长期储存后振摇使用组合物时也不出现“块”以及极大提高的可倾倒性。而且,该组合物是稳定的,例如高达3年的稳定性,而且具有极好的口服施用耐受性。
在一个优选实施方案中,本发明组合物包含抗氧化剂。抗氧化剂可以用于保护奥卡西平不被氧化降解。抗氧化剂可以选自本领域已知的那些化合物中的任一种,例如抗坏血酸、焦亚硫酸钠、谷胱甘肽、或山梨酸。所用抗氧化剂的类型和量可以根据本领域技术人员的一般知识来确定,并可以取决于例如所用奥卡西平的浓度。例如,抗氧化剂如抗坏血酸可以以总组合物0.75-2%(g/ml),如1%的量存在。而且,优选对抗氧化剂的量和类型进行选择以便它不影响(多种)纤维素聚合物或它们的混合物的分散。
也可以使用非前述的其它适合抗氧化剂,只要满足此条件即可。
作为使用抗氧化剂化合物的替代方法,为了降低形成氧化降解产物的可能性,可以通过置换氧(空气)使之不与奥卡西平混悬液接触来实现抗氧化效果。通常,这可以通过在包装时用例如氮气或二氧化碳给装有该混悬液的容器换气来实施。然而,在大体积奥卡西平混悬液(如超过60ml、更具体地约250ml)中,即使仔细清除容器内的空气,也仅仅在相对短的储存期后就可以检测到氧化降解产物。对于小体积的口服混悬液,例如约100ml或更少的奥卡西平,通过仔细地用氮气或其它惰性气体置换容器内空气,可以避免氧化降解产物的形成。当制剂中的氧气被仔细清除后,溶解氧的含量可以少于2mg/ml,例如1mg/ml或更低。
甚至对于大体积的本发明口服混悬液,令人惊奇的是也可以通过按上述方式明智地选择抗氧化剂的类型和量,避免氧化降解产物的形成。无论是否小心清除系统中的空气,情况都可以如此。
考虑某些赋形剂的性质如稳定性,对本发明混悬液的pH进行选择。已经发现,某种pH可以促进氧化降解物的形成,例如抗氧化剂的氧化降解物,如来自抗坏血酸的糠醛的形成。例如,可以调节混悬液如含有抗坏血酸作为抗氧化剂的混悬液的pH,以便它处于pH2-4的范围内,例如pH2.7-3.7。这就使混悬液具有更好的稳定性。
在本发明的再一实施方案中,混悬液可以包含1-20%(g/ml)、如5-7%、如6%的优选微粉化物质形式的奥卡西平。大于40微米(μm)的颗粒的量被限制在最大5%重量,并且通过Fraunhofer衍射得出的平均颗粒大小被规定在4-10μm内。
再一方面,本发明涉及混悬液形式的药物组合物,其包含奥卡西平和少于0.5%(g/ml)的羟乙基纤维素(HEC),例如无HEC。
再一方面,本发明涉及摇溶的口服混悬液形式的药物组合物,其包含6%(g/ml)奥卡西平并在振摇后具有5-52或5-50mPas、如10-40mPas或10-30mPas、如10-25mPas范围内的粘度。
再一方面,本发明涉及混悬液形式的药物组合物,其包含能够以0.3-4ml/秒、如0.4-3ml/秒的速度自由地流出直径3mm孔口的奥卡西平。
适合口服施用的混悬液是基于水的。“基于水的”是指包含水、或水和一种或多种可与水混溶的有机溶剂的混悬液。当使用有机共溶剂时,优选按总组合物的0.5-10%(g/ml)量来使用。适合的溶剂是本领域常用的那些可与水混溶的溶剂,如丙二醇(1,2-丙二醇)、聚乙二醇300、聚乙二醇400和乙醇。这些溶剂也可以是可以任选地在混悬液中用做防腐剂的溶剂。
根据本发明的口服混悬液可以含有通常用于口服混悬液的其它赋形剂,以便提供所要求的稳定性和治疗功效。
赋形剂可以包括:
-防腐剂,例如对羟苯甲酸丙酯、羟苯甲酸甲酯、山梨酸;
-润湿剂,例如聚乙二醇硬脂酸酯、如聚乙二醇400单硬脂酸酯、例如已知的并可从如BASF(德国)购得的商品Cremophor S9泊洛沙姆,聚乙氧基醚;
-甜味剂,如糖精钠、山梨醇溶液,如非结晶的山梨醇溶液;
-调味剂,如黄李柠檬香料(yellow plum lemon aroma),如可从International Flavors and Fragrances(法国)购得。
当需要时,可以从本领域熟知的医药级试剂和溶剂中选择非水溶剂和其它试剂。
至于混悬液制剂中所用任何赋形剂的厂商,本文均未作描述,本发明赋形剂的详情描述在Fiedler的“Lexikon der Hillfstoffe”,第4版,ECVAulendorf 1996和Wade和Weller编的“药物赋形剂手册(Handbook ofPharmaceutical Excipients)”(1994)中,它们的内容特此并入本文作为参考。
根据本发明的典型组合物包含(以质量/体积的%表示):
奥卡西平,微粉化的, 1-20%
例如TRILEPTAL/AS,极
细的
Avicel RC 591 0.1-1.9%
羟苯甲酸甲酯 0.01-1%
聚乙二醇400单硬脂酸酯 0.01-1%
丙二醇(1,2-丙二醇),蒸馏 0.5-10%
的
对羟苯甲酸丙酯 0.005-0.5%
糖精钠,结晶的 0.005-0.5%
山梨酸 0.005-0.5%
山梨醇溶液(非结晶的) 10-40%
抗坏血酸 0.1-10%
水,纯化的 40-85%
黄李柠檬香料 0-15%
除了黄李柠檬香料和聚乙二醇400单硬脂酸酯外,所有的赋形剂均列在USP/NF XXIII中。
本发明制剂可以用于其中掺入了特殊活性剂的已知适应症,例如它们的抗痉挛作用,而且可以作为单独疗法或附加疗法用于抽搐的控制、预防或治疗,例如由于癫痫发作、癫痫持续状态、脑血管疾病、头部损伤和戒酒引起的、有或没有次级泛化的、原发性全面性强直阵挛癫痫和部分性癫痫。
待施用的活性剂和制剂的确切量取决于多种因素,如待治疗的疾病、活性剂的期望持续时间和释放速度。例如,可以基于已知的体外或体内技术测定血浆中特定活性剂的浓度在满意的疗效水平上可以维持多长时间,从而确定活性剂的需要量和其释放速度。
剂量的例子是:对于癫痫症,可以按30mg/kg/天的日维持剂量给儿童施用该口服混悬液。例如,含有300mg奥卡西平的5ml单剂量可以一天最多给予3次。对于成人,日维持剂量为600-1200mg/天。例如,含300mg奥卡西平的5ml单剂量可以一天最多给予4次。
在本发明的另一方面,提供了制备上述定义的口服混悬液的方法。
该方法可以按口服混悬液制备领域所用的常规方式,例如通过在批次中混合混悬液的所有成分,来进行。
制备口服混悬液的方法可以在惰性如不锈钢反应容器中任选地在惰性气体如氮气下进行。
根据本发明制备组合物的方法可以包含以下步骤:
作为预备步骤,通过将优选加热至40-45℃的防腐剂的溶剂和防腐剂混合制备防腐剂溶液(A),并通过将优选加热至45-55℃、或40-50℃的纯化水和润湿剂混合制备分散液(B)。
然后,通过将纯化水和纤维素聚合物如Avicel RC 591混合,制备大批混悬液。然后将所获混合物与溶液(A)混合。可以加入甜味剂或降低微生物活性的试剂如山梨醇溶液。向所获混合物中加入分散液(B)。然后加入抗氧化剂如抗坏血酸,以及任选地调味剂如黄李柠檬香料如黄李柠檬香料39K020或20F和其它甜味剂如糖精钠。加入奥卡西平并搅拌如剧烈搅拌,或匀质化最终的混合物以获得大批口服混悬液(C)。通过以小气泡的形式向分散液通入氮气及稍后通过抽真空抽出残余氮气气泡,使分散液中溶解氧的含量降至最低。
优选将所获口服混悬液在惰性气体下保存,并任选地在重悬后,将其转移至容器如瓶中。装容器的方法讨论如下。
再一方面,本发明涉及包含前述奥卡西平混悬液、填充体积如从约50ml至约300ml的容器。
可以选择用与该口服混悬液不发生反应或基本上不发生反应的材料制作的容器。
尽管优选使用塑料容器,但也可以使用玻璃容器。塑料容器胜于玻璃容器,因为它们重量相对轻而且不易碎因此也更易于储存。对于大体积的混悬液而言,尤其如此。塑料容器主要由热塑性聚合物构成。此外,塑料材料还可以包含添加剂,例如增塑剂、填料、抗氧化剂、抗静电剂和本领域已知用于特殊目的的其它成分。
对于容器系统首要关心的是它们对溶液的UV降解防护。如果需要的话,使用氧化铁的棕色玻璃或与容器吻合的不透明盖子可以提供适当的UV防护。
可以使用各种尺寸的容器。为方便起见可以将容器尺寸分为小体积如100ml或更小及大体积如100ml以上和典型地250ml。鉴于奥卡西平在水中的溶解性相对较低(其溶解性在25℃、pH5.8-6.0下为3.2-4.2mg/ml),优选使用大体积口服混悬液,如100ml以上、更具体地250ml,以便在单个容器中含有有效量的活性剂。
尽管在小体积口服混悬液中使用有机共溶剂可能更优,但小体积口服混悬液提供了更易于储存和使用的优点。而且,用于小体积口服混悬液的容器在填装时具有较小的头部空间,其与大体积口服混悬液所需的较大容器相比含有较少的氧(空气)。由此用于小体积口服混悬液的容器更易于例如使用氮气或其它惰性气体置换出空气。
用于储存本发明口服混悬液的容器可以用于施用多倍剂量的活性剂。用于从容器中将口服混悬液递送至患者体内的装置可以是本领域通常用于从容器(如上述大或小体积容器)中递送出口服混悬液形式的治疗性药剂的任何装置。根据本发明,容器优选包含一个和所述容器匹配的给药注射器。
尽管装置和口服混悬液之间的接触时间可能通常是短暂的,但可以是紧密的,因此应当保证其和口服混悬液相容。因此,该装置的材料可以与容器材料相同,或可以包括通常用于此类装置的其它材料,只要与之的短期接触是可接受的即可。
将口服混悬液装瓶的方法应当在最佳的卫生条件下根据本领域熟知的程序进行。优选地,该方法在空气层流条件下进行。
根据本发明且按上述包装在容器中的口服混悬液对于长期的储存而言是稳定的。
再一方面,本发明涉及治疗癫痫,例如预防或治疗有或无次级泛化的、原发性全面性强直阵挛癫痫和部分性癫痫的方法,该方法包含给需要的对象施用根据本发明的组合物。
再一方面,本发明涉及根据本发明的组合物在治疗癫痫,如在预防或治疗有或无次级泛化的、原发性全面性强直阵挛癫痫和部分性癫痫中的用途。
再一方面,本发明涉及根据本发明的组合物在制备用于预防或治疗有或无次级泛化的、原发性全面性强直阵挛癫痫和部分性癫痫的药物中的用途。
实施例:
实施例1:奥卡西平口服混悬液的制备
通过将事前加热至40-45℃的2.5g丙二醇与0.12g羟苯甲酸甲酯、0.03g对羟苯甲酸丙酯和0.5g山梨酸混合,制备防腐剂溶液(A)。然后,通过将事前加热至45-55℃的0.5-50g纯化水和0.1g聚乙二醇400单硬脂酸酯混合,制备分散液(B)。然后通过将剩余的纯化水(总共达到71.70g)和AvicelRC 591混合,制备散装混悬液。然后将所获混合物与溶液(A)混合。加入25g山梨醇溶液(非结晶的)。然后向所获混合物中加入分散液(B)。然后将抗坏血酸与黄李柠檬香料和糖精钠一起加入。加入奥卡西平并剧烈搅拌此最终混合物以便获得散装口服混悬液(C)。通过以小气泡的形式向分散液中通入氮气及稍后通过抽真空抽出残余氮气气泡,使分散液中溶解氧的含量降低至2mg/L以下。所获口服混悬液在振摇后具有15mPas的粘度。
此所获口服混悬液优选保存在惰性气体下,并任选地在重悬后,根据以上讨论的装瓶方法将之转移至容器如瓶内。
实施例2:混悬液的组成
奥卡西平,微粉化的 6.00g
Avicel RC 591 1.50g
羟苯甲酸甲酯 0.12g
聚乙二醇400单硬脂酸酯 0.10g
丙二醇(1,2-丙二醇),蒸馏的 2.50g
对羟苯甲酸丙酯 0.03g
糖精钠,结晶的 0.05g
山梨酸 0.05g
山梨醇溶液(非结晶的) 25.00g
抗坏血酸 1.00g
水,纯化的 71.70g
黄李柠檬香料39K020 0.25g
————
108.30g(=100ml)
实施例3:
混悬液的组成
TRILEPTAL/AS,超细的 6.00g
Avicel RC 591 1.50g
羟苯甲酸甲酯 0.12g
聚乙二醇400单硬脂酸酯 0.10g
丙二醇(1,2-丙二醇),蒸馏的 2.50g
对羟苯甲酸丙酯 0.03g
糖精钠,结晶的 0.05g
山梨酸 0.05g
山梨醇溶液 25.00g
维生素C 1.00g
水,纯化的 71.70g
黄李柠檬香料20F 0.25g
————
108.30g(=100ml)
Claims (8)
1.混悬液形式的药物组合物,其包含占总组合物5-7%(g/ml)的奥卡西平和占总组合物1.25-1.95%(g/ml)的羧甲基纤维素和微晶纤维素混合物,其中羧甲基纤维素与微晶纤维素在所述混合物中的比是1∶5至1∶12。
2.权利要求1所述的组合物,其中所述混合物中的羧甲基纤维素是钠盐。
3.权利要求1或2的组合物,该组合物还包含抗氧化剂。
4.权利要求1或2的组合物,该组合物还包括抗坏血酸抗氧化剂。
5.权利要求4所述的组合物,其中抗氧化剂占总组合物的0.75-2%(g/ml)。
6.权利要求1所述的组合物,其具有2-4的pH。
7.具有50ml至300ml填充体积的容器,其包含权利要求1-6中任何一项所述的奥卡西平混悬液和与所述容器相配的给药注射器。
8.权利要求1至6所述的组合物在制备预防或治疗有或无次级泛化的、原发性全面性强直阵挛性癫痫和部分性癫痫的药物中的用途。
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-
1999
- 1999-12-20 GB GBGB9930058.4A patent/GB9930058D0/en not_active Ceased
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2000
- 2000-12-12 CO CO00094330A patent/CO5261608A1/es not_active Application Discontinuation
- 2000-12-13 FR FR0016220A patent/FR2802423B1/fr not_active Expired - Lifetime
- 2000-12-14 BE BE2000/0787A patent/BE1013706A5/fr not_active IP Right Cessation
- 2000-12-15 IT IT2000MI002717A patent/ITMI20002717A1/it unknown
- 2000-12-18 AR ARP000106730A patent/AR030175A1/es not_active Application Discontinuation
- 2000-12-18 PE PE2000001359A patent/PE20010933A1/es not_active Application Discontinuation
- 2000-12-19 TR TR2002/01459T patent/TR200201459T2/xx unknown
- 2000-12-19 DK DK00988803T patent/DK1239832T3/da active
- 2000-12-19 TR TR2004/02419T patent/TR200402419T4/xx unknown
- 2000-12-19 WO PCT/EP2000/012968 patent/WO2001045671A2/en active Application Filing
- 2000-12-19 EP EP20040007509 patent/EP1437127A1/en not_active Withdrawn
- 2000-12-19 CA CA2390029A patent/CA2390029C/en not_active Expired - Lifetime
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- 2000-12-19 SK SK865-2002A patent/SK287553B6/sk not_active IP Right Cessation
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- 2000-12-19 NZ NZ518755A patent/NZ518755A/en not_active IP Right Cessation
- 2000-12-19 US US10/168,248 patent/US8119148B2/en not_active Expired - Fee Related
- 2000-12-19 HU HU0203782A patent/HU226486B1/hu unknown
- 2000-12-19 BR BR0016524-7A patent/BR0016524A/pt not_active Application Discontinuation
- 2000-12-19 PT PT00988803T patent/PT1239832E/pt unknown
- 2000-12-19 KR KR10-2004-7015495A patent/KR20040098034A/ko not_active Application Discontinuation
- 2000-12-19 JP JP2001546410A patent/JP4588281B2/ja not_active Expired - Lifetime
- 2000-12-19 RU RU2002119210/15A patent/RU2277912C2/ru active
- 2000-12-19 PL PL355535A patent/PL201331B1/pl unknown
- 2000-12-19 KR KR10-2002-7007846A patent/KR100496368B1/ko active IP Right Grant
- 2000-12-19 EP EP00988803A patent/EP1239832B1/en not_active Expired - Lifetime
- 2000-12-19 DE DE60011809T patent/DE60011809T2/de not_active Expired - Lifetime
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2001
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2002
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- 2002-06-14 NO NO20022849A patent/NO331990B1/no not_active IP Right Cessation
- 2002-06-28 ZA ZA200204863A patent/ZA200204863B/xx unknown
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2003
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2006
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